Neuroscience Learning and Memory Quiz

Synaptic Plasticity & Learning

• Synaptic plasticity is activity-dependent changes in synaptic strength
• Short-term plasticity: alterations lasting a few minutes or less, involving changes in synaptic transmission, varying in their time course and mechanisms; most altering transmitter release amounts
• Long-term plasticity: alterations lasting 30 minutes or longer, including long-lasting strengthening or weakening of synaptic strength in mammalian brains (e.g., LTP, LTD), altering circuit function and potentially relating to learning and memory
• Ongoing activity can result in short-term changes in synaptic efficacy via transmitter release

Synaptic Facilitation, Depression & Interaction

• Synaptic facilitation: an enhanced response to a repeated stimulus, with subsequent responses increasing in magnitude
• Synaptic depression: a weakening response to repeated stimulation, with subsequent responses decreasing in magnitude
• Interaction involves both facilitation and depression, creating a net affect on synaptic responses

Post-Tetanic Potentiation (PTP)

• PTP is stimulated by longer high-frequency trains of stimuli, which elicits synaptic depression, but a few seconds later elicits an increase in postsynaptic potential (PSP) amplitude.
• PTP lasts for tens of minutes

Activity-Dependent Changes in Synaptic Efficacy

• Long-term potentiation (LTP): a sustained enhancement of synaptic strength, dependent on activity; a long-lasting increasing synaptic strength
• Long-term depression (LTD): a persistent reduction in synaptic strength, also activity-dependent; a long-lasting decrease in synaptic strength
• Both LTP and LTD are broad terms referring to various diverse mechanisms

Trisynaptic Circuit: Dentate Gyrus

• Defined, unidirectional information flow through the hippocampus, facilitating targeted stimulation to study synaptic function.
• The circuit involves the dentate gyrus, CA3, and CA1 pyramidal cells, with inputs from the entorhinal cortex and outputs to other regions

Bliss & Lomo (1973)

• Bliss and Lomo demonstrated that tetanic stimulation in the perforant path produced potentiated responses lasting hours (by increasing EPSP amplitude in the dentate granule cells).

Important Properties of LTP

• Experience-dependent: LTP requires specific stimulation to produce a notable change in strength
• Induced rapidly: a few seconds of stimulation can lead to lasting effects lasting hours
• Cooperativity: a threshold intensity of stimulation is needed for the induction of LTP
• Coincident activity: the coordinated activation of pre- and postsynaptic cells is necessary for LTP induction
• Input Specificity: only activated pathways are potentiated
• Associativity: simultaneous activation of separate but converging inputs produces LTP if occurring in a close temporal sequence

Experimental Evidence for 3 Properties of LTP

• S2 stimulation alone is insufficient to induce LTP, falling below the cooperativity stimulus intensity threshold

Experimental Evidence for 3 Properties of LTP (input specificity)

• SI stimulation is sufficient to induce LTP at the synapses stimulated, but not at others

Experimental Evidence for 3 Properties of LTP (associativity)

• Simultaneous tetanus to both inputs allowed the weak input to benefit from the strong input

Coincident Activity

• A single pulse to Schaffer collateral axons does not induce LTP on its own.
• However, LTP is induced if the pulse is linked/paired with depolarization of the CA1 cell via a recording electrode

LTP as a Cellular Analog of Associative Learning

• Before learning, a weak input (NS) is not potent enough, but the strong input (US) is sufficient.
• During learning, the weak and strong inputs are sequentially paired, inducing a change in synaptic strength (LTP).
• After learning, the weak input now elicits a response independently

How Long Can LTP Last?

• The longest in-vivo experiment lasted up to 1 year.
• The duration depends on the number of stimulation trains.
• LTP can potentially serve as a mechanism for long-lasting information storage.

Long-Term Depression (LTD)

• Repetitive low-frequency stimulation can reduce the size of postsynaptic potentials (EPSPs), inducing LTD.

Important Features of LTD

• Similar to LTP, LTD can last for several hours and show input specificity.
• It can be considered the opposite of LTP, reducing connections between brain regions or cells.
• LTD can reverse LTP-induced EPSP increases.
• It occurs through a complementary mechanism in synapses where LTP acts (by acting in the common synapse location)

Explaining LTP Features

• This section discusses underlying mechanisms to understand LTP properties, such as cooperativity.

LTP Often Depends on Activation of NMDA Receptors

• Drugs that block NMDA receptors impair LTP induction without affecting baseline responses.

The NMDA Receptor as a Coincidence Detector

• The NMDA receptor channel opens only when glutamate is bound to the receptor and the postsynaptic cell is depolarized (relieving the Mg2+ block) simultaneously.

Different Mechanisms Underlying LTP Phases

• Short-Term Potentiation (STP) (induction): minutes to 1 hour, NMDA receptor and postsynaptic Ca2+ dependent.
• Early-LTP (E-LTP) (expression): 1-5 hours, protein kinase dependent (but not protein synthesis dependent).
• Late-LTP (L-LTP) (maintenance): many hours to years, protein synthesis and RNA transcription dependent.

Increased Ca2+ in the Postsynaptic Cell

• Increased intracellular calcium ([Ca2+]) in the postsynaptic cell triggers LTP induction.
• This occurs through signal transduction cascades involving CaMKII and PKC.
• Blocking Ca2+ chelators prevents LTP induction, accounting for the first hour of LTP.

How is LTP Actually Expressed?

• Synaptic strengthening during LTP arises from an increase in the sensitivity of the postsynaptic cell to glutamate and requires at least 6 mechanisms, expressed on either the pre- or postsynaptic sides of the synapse

Activation of Silent Synapses

• Activation of silent synapses is one major factor responsible for postsynaptic expression of early-LTP
• Silent synapses (which initially lack AMPA receptors) become active by inserting AMPA receptors after LTP induction.

Late-LTP Depends on Gene Expression

• Late-LTP involves changes in gene expression and synthesis of new proteins.
• These proteins maintain the potentiation.

Long-Lasting LTP Changes

• New dendritic spines can be observed as early as one hour after a stimulus.
• Shortening/widening of spine necks reduces electrical resistance, increasing synaptic efficacy.

LTD Mechanisms

• Similar to LTP, LTD requires NMDA receptor activation and Ca2+ entry for induction.
• However, small and slow increases in Ca2+ lead to LTD, while rapid increases lead to LTP.
• Activation of Ca2+-dependent phosphatases and loss (internalization) of AMPA receptors are integral to LTD.

Summary of Important Concepts (general overview)

• Short periods of synaptic activation result in facilitation, depression, or augmentation of transmitter release.
• Facilitation decays rapidly, while depression and augmentation persist.
• Facilitation relates to increased cytoplasmic calcium concentration in the presynaptic terminal.
• Longer periods induce post-tetanic potentiation (PTP) of transmitter release, mediated by presynaptic terminal calcium concentration increase
• Repetitive stimulation can lead to activity-driven LTP or LTD in various CNS parts, with effects being homo- or heterosynaptic.
• LTP enhances synaptic efficacy by increasing calcium concentration, inserting new receptors, and increasing receptor sensitivity in the postsynaptic cell.
• LTD reduces efficacy by decreasing calcium concentration, potentially through decreasing or internalizing receptors

Summary of Important Concepts (LTP as a memory)

• LTP is a measurable event in synaptic efficacy, a response to experiences.
• Blocking LTP during learning impairs memory.
• Altering synaptic weight changes that result from learning can alter memory.
• Mimicking LTP can induce memory from past events that did not truly happen.

Does Learning Induce LTP?

• Two-chambered box (light and dark): an experimental setup for learning where an animal learns to avoid the shock-associated side.
• Inhibitory Avoidance Paradigm: animals learn to avoid the shock side based on the latency to enter
• Control groups are essential to rule out alternative explanations.

Learning-Induced LTP

• Whitlock et al. (2006) used the inhibitory avoidance paradigm to show that learning enhances phosphorylation and increases GluR1 and GluR2 protein levels, indicative of LTP induction.

Learning-Induced LTP (water maze)

• In water maze studies, HPC-lesioned rats demonstrated an increased latency to find the escape platform. This indicates that the hippocampus is essential for spatial reference memory and performance.
• Transfer tests assess location preferences (quadrant preference) when the platform is absent; indicating that animals still have spatial knowledge of the maze even without the cue of the platform.
• LTP could be a neural mechanism underpinning learning.

Learning-Induced LTP (Cellular Markers)

Additional markers indicated LTP occurred after avoidance training including increases in GluR1 and GluR2 protein expression and phosphorylation of receptors

Inhibitory Avoidance Learning Induced LTP

• Learning induces a fairly weak change in fEPSPs in CA1.
• The weak change is clear to demonstrate a response in-vivo, but some effects in the population may be concealed due to an uneven sampling distribution.

Preventing LTP Before/During a Learning Experience

• Preventing or blocking LTP during learning can impair learning and memory.

Water Maze (spatial reference memory)

• Rats are trained to find a hidden platform in a water maze.
• HPC-lesioned rats demonstrated an increased latency in finding the platform, indicating a hippocampal function for spatial reference memory.
• Transfer tests measures location preference when the platform is absent.

Preventing LTP

• Targeting NMDA receptors using AP5 blocks NMDA receptors, impacting downstream signaling and preventing LTP induction.
• Blocking LTP induces problems in spatial learning and memory

Water Maze Performance with AP5

• Intraventricular administration of AP5 (an NMDA receptor antagonist) blocks LTP induction in the hippocampus.
• AP5 causes increased latency in finding the platform during training.
• AP5 impairs the memory of platform location during transfer tests

Water Maze Performance in CaMKII Mutants

• CaMKII knockout mice have impaired spatial tasks (in finding a visible platform), but this deficiency isn't directly due to hippocampal lesions.

Preventing LTP (methods)

• Targeting NMDA receptors or disrupting downstream intracellular signaling involving CaMKII, and preventing AMPA receptor expression are methods for inhibiting LTP

Genetic Manipulation of AMPARs

• Genetic manipulation of AMPA receptors (e.g., knockout of GluA1 subunit) impairs LTP in the CA3→CA1 synapses.

Spatial Reference Memory in CA1-NR1 KOs

• Impairment of LTP is restricted to the CA1 region, where spatial reference memory is not affected (measured by behavioral tasks)

T-Maze (rewarded alternation)

• A test of spatial working memory.
• Complete and dorsal hippocampus lesions impair T-maze rewarded alternation performance.

T-Maze Alternation Performance with GluA1 KO Mice

• GluA1 knockout mice exhibit T-maze alternation deficits but show normal water maze ability.
• This highlights the specificity of AMPA receptors for certain types of memory.

Preventing LTP (summary)

• Methods exist to target NMDA receptors to prevent LTP induction and Go-downstream to prevent intracellular signaling, including targeting CaMKII, and targeting AMPA receptors

CA1-Specific Genetic KO of NR1

• NR1 knockout has a restricted effect specifically on the CA1 region.
• The effect on the CA1 region is visible with impaired performance in a water maze task

Spatial Reference Memory in DG-NR1 KOS

• Spatial reference memory is unaffected in DG-NR1 KOs. These mice are impaired in spatial working memory.

Hippocampal LTP

• Hippocampal LTP isn't always a reliable measure of spatial learning and memory formation, as inhibiting it may not impair memory formation completely (some memories might have been created before interfering with LTP).

Is LTP Really a Memory Mechanism?

• LTP may not fully account for all aspects of memory, as memories can persist even after LTP decays.
• Research into alternative mechanisms of memory is ongoing.